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A. Kritharis et al.
review focuses on the biology of HHT and the manage- ment issues that confront the hematologist, as well as pro- posing a hematology management scheme.
Pathogenesis
Pathology
Hereditary hemorrhagic telangiectasia is a disease char- acterized by vascular lesions, including AVMs and telang- iectasias. AVMs are abnormal connections that form between arteries and veins without an intermediary capil- lary system. They can occur anywhere in the body, such as in the central nervous system (CNS), lungs, liver or spine. Vascular malformations may be composed of small (nidi 1-3 cm) or micro (nidi <1 cm) AVMs, pulmonary sacs, or direct high-flow connections. While the terms “telang- iectasia” and “arteriovenous malformation” are often used interchangeably, as they both occur from a direct connec- tion between an artery and a vein whilst bypassing the capillary system, they are actually pathologically-distinct terms. Telangiectasias, by definition, occur on mucocuta- neous surfaces, such as the skin, gastrointestinal (GI) mucosa, or upper aerodigestive tract. AVMs occur in inter- nal organs, such as the liver, lung, and brain.9 Histological evaluation of AVMs reveals an irregular endothelium, increased collagen and actin, and a convoluted basement membrane.10
Gene mutations
Gene mutations that have been described in HHT include ENG, ACVRL1 (also known as ALK1), and MADH4 (also known as SMAD4), as well as other postu- lated loci (Table 1).11,12
• In 1994, ENG, located on chromosome 9q34 and encoding for the protein endoglin (CD105), was the first gene identified in which mutations resulted in HHT, and so HHT due to ENG mutations is known as HHT type 1 (HHT1).13 Endoglin is a cell-surface glycoprotein that func- tions as part of the transforming growth factor beta (TGF- β) signaling complex that plays an important role in angio- genesis and vascular remodeling.14,15
• In 1996, defects in the ACVRL1 gene on chromosome 12q13, which encodes for the activin receptor-like kinase 1 (ALK1), were recognized to cause HHT, and defects in this gene result in HHT type 2 (HHT2). Like endoglin, ALK1 is a cell-surface protein that is part of the TGF-β sig- naling pathway and is important in the regulation of angiogenesis.16
• Mutations in MADH4 (which encodes for the SMAD4 protein, a transcription factor that mediates signal trans- duction in the TGF-β pathway17) result in a juvenile poly- posis with HHT syndrome (JP-HHT), described later in this review.
Over 80% of HHT patients have identifiable mutations,18,19 leaving approximately 20% who meet clin- ical diagnostic criteria but do not have definitive muta- tions. Of those with a pathogenic mutation, 61% have ENG mutations, 37% have ACVRL1 mutations, and 2% have MADH4 mutations;20 very small minorities of patients have pathogenic mutations in other genes, described below. Over 600 different mutations have been uncovered in ENG and ACVRL1 in all exons as well as exon/intron boundaries and splice-sites.21 Frameshift and nonsense mutations appear to be more frequent in ENG.
Additional loci associated with HHT have been identi- fied on chromosomes 5q31 (HHT3) and 7q14 (HHT4), but have not been completely characterized.20,22,23 Bone mor- phogenetic protein 9 (BMP9, also known as growth differ- entiation factor 2 or GDF2), encoded by BMP9 (also called GDF2), is a ligand for the ACVRL1 gene product ALK1. Consequently, mutations in BMP9/GDF2 result in the clinical manifestations of HHT and are referred to as HHT- 5. In addition, pathogenic mutations in the RASA1 gene have also been associated with a clinical syndrome consis- tent with HHT24 as well as other vascular anomalies. Little is known about RASA1-mutated HHT.
Pathophysiology
All three identified causative genes are involved in cell signaling via the TGF-β/BMP signaling pathway, which has roles in cell growth, apoptosis, smooth muscle cell dif- ferentiation, and vascular remodeling and maintenance.25 The vasculature normally develops from the capillary sys- tem with the activation and growth of endothelial cells, the intercellular junctions between them, and the matura- tion of the basement membrane.26 Capillaries then devel- op into larger vessels with the recruitment of smooth muscle cells to the endothelial wall where TGF-β is essen- tial.
In the healthy patient, ligands in the extracellular space such as TGF-β, activins and BMPs bind to type I and type II serine/threonine receptors of the cell membrane. TGF- β1/2/3 ligand binds to the type II receptor of the TGF-β signaling cascade (TGFβRII) that becomes phosphorylated and recruits the TGF-β type I receptors ALK1 or ALK5.27 Endoglin is an endothelial specific receptor that associates
Table 1. Classification and genetics of the most common hereditary human telangiectasia (HHT) subtypes.
Disease
HHT type 1
HHT type 2
Combined syndrome of HHT and JP-HHT
Genetic mutation (locus)
ENG (9q34.11)
ACVRL1 (ALK1;12q13.13)
MADH4 (SMAD4; 18q21.2)
Primary visceral manifestations
Pulmonary AVMs Brain AVMs
Liver AVMs
Pulmonary hypertension Spinal AVMs
Gastrointestinal polyps AVMs
Pulmonary hypertension
Function of normal gene product
Membrane glycoprotein receptor on
endothelial cells, part of the transforming growth factor- beta (TGF-β) receptor complex
Activin receptor-like kinase 1 (ALK1), a cell-surface serine/threonine-protein kinase receptor, part of the TGF-β receptor complex
MADH4 encodes SMAD4, a transcription factor acting as a mediator in the TGF-β/BMP pathway signaling
AVM: arteriovenous malformations; JP-HHT: juvenile polyposis-HHT.
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haematologica | 2018; 103(9)